Apoptosis, a mode of cell death reported in the 1970s, differs from necrosis and is a cell death induced through a specific intracellular signal transduction system [Cell, 88, 355–365 (1997)]. Apoptosis is involved in pathologic conditions of variety of diseases. A control of apoptosis may possibly contribute to progresses of therapeutic treatments of these diseases. For example, a deviation from a normal apoptosis control mechanism and a resulting acceleration of cell death are believed to induce articular rheumatism, hepatitis with viral infection such as hepatitis B and C, fulminant hepatitis, diabetes, myocardial infarction, ulcerative colitis, brightism, alopecia, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, ischemic brain damage, acquired immune deficiency syndrome, ecstatic cardiomyopathy and the like [Science, 267, 1456–1462 (1995)].
Examples of physiological stimulation inducing apoptosis include Fas/Apo-1/CD95 ligand, Fas antibody, TNF (tumor necrosis factor) and the like [Cell, 88, 355–365 (1997)]. As compounds suppressing apoptosis, various peptide caspase inhibitors as cysteine protease inhibitors and the like are known; however, the compounds have problems in instability inherent to peptide compounds and insufficient potency.
Antitumor agents clinically used at present can achieve temporal retraction or disappearance of cancers on the basis of their cytotoxicity. However, as they act on healthy cells to cause serious adverse effects, their applications are much limited. In addition, among gastric cancers, colon cancers, pancreatic cancers and the like, there are a number of naturally resistant cancers to which anticancer agents are almost ineffective, or appearance of acquired resistant cancer cells to which primarily effective anticancer agents become ineffective, which causes a serious problem.
Recently, so-called tumor angiogenesis for supplying nutriment and oxygen to cancer cells has been focused as a mechanism of solid cancer proliferation beyond a certain size. An idea of “a therapy by inhibition of tumor angiogenesis” has been being established in which cancer proliferation is suppressed by inhibiting tumor angiogenesis [European Journal of Cancer, 32A, 2534–2539 (1996)]. Although a number of compounds have already been practically developed as antitumor agents, clinical uses of an angiogenesis inhibitors as early as possible have been desired, because they have advantages that conventional antitumor agents do not have. Some angiogenesis inhibitors have been developed and studied so far; however, novel compounds as potential lead compounds have always been desired strongly.
A recruit mechanism of vascular endothelial cells into a cancer tissue has a number of similarities to a recruit mechanism of leukocytes and the like into inflammatory sites, and therefore, medicaments inhibiting chemotaxis of vascular endothelial cells are expected to have potentials as anti-inflammatory agents as well as angiogenesis inhibitors [Immunity, 12, 121–127 (2000)].